chr2-138002090-G-A

Position:

• chr2-138002090-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_006895.3(HNMT):​c.325G>A​(p.Glu109Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000377 in 1,593,058 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00039 (4 hom.)
• Consequence: HNMT NM_006895.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 1.69

Genes affected

HNMT (HGNC:5028): (histamine N-methyltransferase) In mammals, histamine is metabolized by two major pathways: N(tau)-methylation via histamine N-methyltransferase and oxidative deamination via diamine oxidase. This gene encodes the first enzyme which is found in the cytosol and uses S-adenosyl-L-methionine as the methyl donor. In the mammalian brain, the neurotransmitter activity of histamine is controlled by N(tau)-methylation as diamine oxidase is not found in the central nervous system. A common genetic polymorphism affects the activity levels of this gene product in red blood cells. Multiple alternatively spliced transcript variants that encode different proteins have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010490447).
• BP6: Variant 2-138002090-G-A is Benign according to our data. Variant chr2-138002090-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 721467.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HNMT	NM_006895.3	c.325G>A	p.Glu109Lys	missense_variant	4/6	ENST00000280097.5	NP_008826.1
HNMT	XM_017003948.2	c.223G>A	p.Glu75Lys	missense_variant	4/6		XP_016859437.1
HNMT	XM_017003949.3	c.325G>A	p.Glu109Lys	missense_variant	4/5		XP_016859438.1
HNMT	XM_011511064.3	c.-54G>A		5_prime_UTR_variant	3/5		XP_011509366.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HNMT	ENST00000280097.5	c.325G>A	p.Glu109Lys	missense_variant	4/6	1	NM_006895.3	ENSP00000280097	P1
HNMT	ENST00000410115.5	c.325G>A	p.Glu109Lys	missense_variant	5/7	5		ENSP00000386940	P1
HNMT	ENST00000467390.5	n.337G>A		non_coding_transcript_exon_variant	4/5	2
HNMT	ENST00000485653.1	n.257G>A		non_coding_transcript_exon_variant	3/5	5

Frequencies

GnomAD3 genomes AF: 0.000296 AC: 45 AN: 152022 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00394

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.000480

GnomAD3 exomes AF: 0.000544 AC: 130 AN: 239066 Hom.: 0 AF XY: 0.000681 AC XY: 88 AN XY: 129264

Gnomad AFR exome AF: 0.0000640

Gnomad AMR exome AF: 0.0000638

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000114

Gnomad SAS exome AF: 0.00367

Gnomad FIN exome AF: 0.000513

Gnomad NFE exome AF: 0.000109

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000385 AC: 555 AN: 1440918 Hom.: 4 Cov.: 29 AF XY: 0.000539 AC XY: 386 AN XY: 716202

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000239

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000512

Gnomad4 SAS exome AF: 0.00451

Gnomad4 FIN exome AF: 0.000699

Gnomad4 NFE exome AF: 0.000102

Gnomad4 OTH exome AF: 0.000404

GnomAD4 genome AF: 0.000296 AC: 45 AN: 152140 Hom.: 0 Cov.: 32 AF XY: 0.000363 AC XY: 27 AN XY: 74372

Gnomad4 AFR AF: 0.0000963

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00394

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.000475

Alfa AF: 0.000182 Hom.: 0

Bravo AF: 0.000113

ExAC AF: 0.000651 AC: 79

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Intellectual disability, autosomal recessive 51 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Sep 08, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	18
DANN	Benign	0.96
DEOGEN2	Benign	0.041	T;T
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.78	.;T
M_CAP	Benign	0.0070	T
MetaRNN	Benign	0.010	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.96	L;L
MutationTaster	Benign	0.99	N;N
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.30	N;N
REVEL	Benign	0.035
Sift	Benign	0.24	T;T
Sift4G	Benign	0.27	T;T
Polyphen		0.0010	B;B
Vest4		0.21
MVP		0.37
MPC		0.068
ClinPred		0.012	T
GERP RS		3.0
Varity_R		0.23
gMVP		0.36

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs528223406; hg19: chr2-138759660; COSMIC: COSV54508326;